Novel Agents Lead to Changes in Therapeutic Strategies and Sequencing for CLL

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A shift in treatment patterns has occurred since the introduction of novel targeted agents for chronic lymphocytic leukemia (CLL), according to study results presented at the 2021 American Society of Hematology (ASH) Annual Meeting.

Researchers evaluated the outcomes of patients treated with chemoimmunotherapy (CIT) combinations as first-line treatment compared with Bruton tyrosine kinase inhibitors (BTKi), evaluated the efficacy and tolerability of venetoclax-based regimens, and assessed the effects of treatment sequencing of chemotherapy-free options in patients with CLL.

Data were analyzed from patients diagnosed with CLL between 2000 and 2020 from 77 institutions affiliated with the European Research Initiative on CLL (ERIC). A total of 9173 patients who had received at least 1 line of treatment were included. Participants had a median age at diagnosis of 67 years, and 65% were men. The median follow-up was 78 months (interquartile range, 48-120 months).


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Of the cohort, 1860 (20.2%) patients had received at least 1 line of treatment with a BTKi (ibrutinib, 1788 patients; acalabrutinib, 72 patients), 631 (6.9%) with venetoclax, and 447 (4.9%) with the PI3K inhibitor idelalisib. At last follow-up, 5870 patients (64.0%) were alive, 3229 (35.2%) had died, and 74 (0.8%) were lost to follow-up.

Patients who received a BTKi as first-line treatment were enriched for TP53 aberrations (del[17p] 27.6%, TP53 mutation 26.3%) and unmutated IGHV (69%). They had an overall response rate (ORR) of 87.7%. Of this group, 136 (26.3%) discontinued treatment after a median of 1.2 years (0.07-5.98), owing to toxicity in 40.5% and failure in 26.2%.

In the 631 patients treated with venetoclax in any line, 100 (15.8%) received BCL2 ± anti-CD20 therapy as first-line treatment, 170 (26.9%) as second-line treatment (125 previously treated with CIT, 27 with BTKi), and 361 as a third or subsequent line of treatment. The ORR with third- or subsequent-line treatment was 71.5%, with a 30.5% rate of complete remission (CR) or CR with incomplete hematologic recovery (CRi). The ORR with second-line therapy was 94%, with a 58% CR/CRi rate. The ORR with first-line treatment was 90.3%, with a 68.1% CR/CRi rate.

Treatment discontinuation was due to toxicity in 28.6% of patients with first-line treatment, 17.6% with second-line treatment, and 21.8% with third- or higher-line treatment. Disease progression resulted in treatment discontinuation in 14.3%, 20.6%, and 33.6% of participants with first-line, second-line, and third- or higher-line treatment, respectively.

A total of 199 patients were treated with a BTKi and venetoclax. The ORR for patients who received venetoclax after a BTKi (175 patients) was 73.7% (30.8% CR/CRi), and the ORR for those who received a BTKi after venetoclax (24 patients) was 66% (20.8% CR/CRi).

CIT was used as front-line treatment in 5465 patients (59.6%), of whom 2070 (37.9%) received a second line of treatment and 1018 (18.6%) received a third line of treatment. A total of 865/1086 patients (79.7%) who had a second line of treatment before 2014 were retreated with CIT, most frequently bendamustine-rituximab (284/1086, 26.1%) and fludarabine-cyclophosphamide-rituximab (252/1086, 23.2%). Alemtuzumab monotherapy was given to 55 (5%) patients.

After 2014, 415/984 patients (42.1%) were retreated with a BTKi, 93 (9.5%) with venetoclax, 70 (7.2%) with idelalisib, 50 (5%) with alemtuzumab monotherapy, and 315 (32%) with CIT. Regarding third- or higher-line treatment, 86.3% of participants were retreated with CIT before 2014, and BTKi, BCL2i, and PI3Ki were used mainly after 2014 (in 43.1%, 15.7%, and 14.7% of cases, respectively).

Among 1075 patients with TP53 aberrations, the ORR for those receiving BTKis (171 patients) as first-line treatment was 86.5% (22.2 CR + 64.3 PR), and the ORR with venetoclax ± anti-CD20 (15 patients) was 91% (45.5% CR + 45.5 PR). Patients treated with CIT (694 patients) had an ORR of 68.7% (28.3% CR + 40.4% PR).

The researchers concluded that patients who failed on venetoclax can be rescued with a BTKi and vice versa.

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

Read more of Cancer Therapy Advisor’s coverage of the ASH 2021 meeting by visiting the conference page.

Reference

Chatzikonstantinou T, Scarfo L, Demosthenous C, et al. Real-world evidence on therapeutic strategies and treatment-sequencing in patients with chronic lymphocytic leukemia: an international study of ERIC, the European Research Initiative on CLL. Presented at ASH 2021; December 11-14, 2021. Abstract 2635.



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